Association between caffeine intake and age at onset in Huntington's disease

Simonin, C.; Duru, Cécile; Salleron, Julia; Hincker, P; Charles, Perrine; Delval, Arnaud; Youssov, Katia; Burnouf, Sylvie; Azulay, Jean‐Philippe; Verny, Christophe; Scherer, Clarisse; Tranchant, C.; Goizet, Cyril; Debruxelles, Sabrina; Defebvre, Luc; Sablonnière, Bernard; Romon-Rousseaux, Monique; Buée, Luc; Destée, Alain; Godefroy, Olivier; Dürr, Alexandra; Landwehrmeyer, G. Bernhard; Bachoud‐Lévi, Anne‐Catherine; Richard, Florence; Blum, David; Krystkowiak, Pierre

doi:10.1016/j.nbd.2013.05.013

Cited by 67 publications

(56 citation statements)

References 21 publications

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“…Other studies have reported that environmental factors such as increased caffeine intake [35] and more time spent in education [22] are also associated with an earlier age of onset. Despite this, the question whether early behaviour can impact upon the profile of disease experienced in later life is an interesting one and warrants further investigation.…”

Section: Lifestyle Factorsmentioning

confidence: 98%

Progress in Huntington’s disease: the search for markers of disease onset and progression

Mason

Barker

2015

J Neurol

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Unlike most neurodegenerative disorders, individuals at risk from Huntington's disease can be identified prior to the onset of clinical signs of the disease by virtue of it being an autosomal dominant condition. This provides the hypothetical opportunity to delay disease onset and/or slow down the progression of the disease in the very early stages ahead of overt features of disease. To help prepare for therapeutic trials of disease-modifying compounds, extensive work has gone into (1) finding ways of better predicting the onset of disease in pre-manifest HD gene carriers (PMGC), (2) defining the extent of non-motor features of HD and (3) identifying robust and reliable tests by which to measure disease progression. In this short review, we summarise some of the major findings in this area of clinical research.

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Section: Lifestyle Factorsmentioning

confidence: 98%

Progress in Huntington’s disease: the search for markers of disease onset and progression

Mason

Barker

2015

J Neurol

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“…149 Caffeine is a nonselective A 1 R and A 2A R antagonist, and it is proposed that the blockade of these receptors by caffeine may result in an increased acceleration of neurodegeneration. This could possibly be related to the fact that chronic caffeine exposure is associated with tolerance to the A 1 R but not to the A 2A R. 150 Studies show that high doses of A 2A R antagonists or global genetic A 2A R blockade worsen disease progression in HD models, 151,152 whereas A 2A R agonists as well as A 1 R agonists have been shown to protect against neurodegeneration.…”

Section: Striatal Adenosine Neurotransmissionmentioning

confidence: 99%

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

Blum

Chern

Domenici

et al. 2018

Journal of Caffeine and Adenosine Research

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A 2A receptors (A 2A R), suggesting a possible involvement of adenosine and A 2A R is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A 2A R dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.Keywords: Huntington's disease, adenosine, adenosine receptors, equilibrative nucleoside transporter, animal models Pathogenic Mechanisms of Huntington's DiseaseOverview H untington's disease (HD) is an inherited neurodegenerative disorder that is caused by a single, autosomal dominant gene mutation. HD generally affects young adults and is characterized by involuntary, abnormal movements and postures (chorea, dyskinesia, dystonia), psychiatric disturbances, and cognitive alterations.1,2 It is estimated that 1 in 10,000 people have HD and this disorder is fatal within 15-20 years after the onset of symptoms. Multiple brain regions, including several cortical and subcortical regions (cerebral cortex, layers III, V, and VI; pallidum, sub-thalamic nucleus, cerebellum), show signs of neurodegeneration, but the most pronounced neuronal loss is present in the caudate nucleus and the putamen of the striatum.3 Within the striatum, the striato-pallidal, medium spiny neurons (MSN) that express enkephalin, dopamine D 2 receptors (D 2 R) and adenosine A 2A receptors (A 2A R), 4,5 appear to be the most vulnerable.6,7

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“…In fact, tonic activation of A 2A R is necessary for the action of brain-derived neurotrophic factor (BDNF; Diogenes et al, 2004; Rodrigues et al, 2014), which is greatly impaired during HD progression (Zuccato et al, 2001). Finally, genetic and epidemiological studies also support the involvement of A 2A R. Several polymorphisms in the A 2A R gene have been associated to a reduced age of onset of the disease (Dhaenens et al 2009; Taherzadeh-Fard et al, 2010) and, in a recent study, caffeine (non-selective adenosine receptor antagonist) intake (more than 190 mg/day) was significantly associated with a reduced age of onset of HD by about 4 years (Simonin et al, 2013). Apart from these findings involving specifically A 2A R, diverse alterations in other adenosine receptor subtypes and in adenosine homeostasis have also been documented in animal models of HD (Lee and Chern, 2014).…”

Section: Introductionmentioning

confidence: 96%

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease

Guitart

Bonaventura

Rea

et al. 2016

Neurobiology of Disease

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The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENT1) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [3H]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENT1 binding sites were significantly upregulated in zQ175 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENT1 transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENT1 and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease.

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Association between caffeine intake and age at onset in Huntington's disease

Cited by 67 publications

References 21 publications

Progress in Huntington’s disease: the search for markers of disease onset and progression

Progress in Huntington’s disease: the search for markers of disease onset and progression

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease

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